Novel esterified cellulose ethers of very high molecular weight

ABSTRACT

Esterified cellulose ethers which comprise (i) groups of the formula —C(O)—R—COOA or (ii) a combination of aliphatic monovalent acyl groups and groups of the formula —C(O)—R—COOA, wherein R is a divalent aliphatic or aromatic hydrocarbon group and A is hydrogen or a cation, which have a viscosity of up 50 mPa·s, measured as a 10 wt % solution of the esterified cellulose ether in acetone at 20° C., and a weight average molecular weight M w  of at least 220,000 Dalton, or which have a viscosity of up 100 mPa·s, measured as a 10 wt % solution of the esterified cellulose ether in acetone at 20° C., and a weight average molecular weight M w  of at least 310,000 Dalton are useful for preparing solid dispersions comprising drugs.

FIELD

This invention concerns novel esterified cellulose ethers, soliddispersions of an active ingredient in such esterified cellulose ether,as well as liquid compositions, coated dosage forms and capsulescomprising such esterified cellulose ether.

INTRODUCTION

Esters of cellulose ethers, their uses and processes for preparing themare generally known in the art. Known methods of producing celluloseether-esters include the reaction of a cellulose ether with an aliphaticmonocarboxylic acid anhydride or a dicarboxylic acid anhydride or acombination thereof, for example as described in U.S. Pat. Nos.4,226,981 and 4,365,060.

Various known esterified cellulose ethers are useful as enteric polymersfor pharmaceutical dosage forms, such as methylcellulose phthalate,hydroxypropyl methylcellulose phthalate, methylcellulose succinate, orhydroxypropyl methylcellulose succinate. Dosage forms coated with suchpolymers protect the drug from inactivation or degradation in the acidicenvironment or prevent irritation of the stomach by the drug. U.S. Pat.No. 4,365,060 discloses enterosoluble capsules which are said to haveexcellent enterosolubility behavior.

US Patent Application Publication No. 2004/0152886 discloses theproduction of hydroxypropyl methylcellulose phthalate starting fromhydroxypropyl methylcellulose having a viscosity of 3 to 20 cp, measuredas a 2 wt. % aqueous solution.

International patent applications WO 2005/115330 and WO 2011/159626disclose the preparation of hydroxypropyl methylcellulose acetatesuccinate (HPMCAS). HPMC having an apparent viscosity of 2.4 to 3.6 cpis recommended as a starting material. Alternatively, a HPMC startingmaterial of 600 to 60,000 Daltons, preferably 3000 to 50,000 Daltons,more preferably 6,000 to 30,000 Daltons is recommended. According toKeary [Keary, C. M.; Carbohydrate Polymers 45 (2001) 293-303, Tables 7and 8] HPMC having a weight average molecular weight of about 85-100 kDahas a viscosity of about 50 mPaxs, determined as a 2% by weight aqueoussolution.

U.S. Pat. No. 5,776,501 teaches the usage of a water-soluble celluloseether having a viscosity of 3 to 10 cp (mPa·s), determined as a 2% byweight aqueous solution. If the viscosity is less than 3 cp, the finallyobtained coating film for solid enteric pharmaceutical preparations isinsufficient in strength, while if it exceeds 10 cp, the viscosityobserved when it is dissolved in a solvent to carry out a substitutionreaction becomes extremely high.

European Patent Application EP-A-0 219 426 discloses a method forpreparing an enteric-soluble acidic dicarboxylic acid ester of acellulose ether which is produced from a cellulose ether having aviscosity of at least 5 cp, measured as a 2% by weight aqueous solutionat 20° C. A HPMCAS produced from a HPMC of 6 cp viscosity had a highermolecular weight and a good resistance against a simulated gastric juicethan a HPMCAS produced from a HPMC of 3 cp viscosity, whichdisintegrated in simulated gastric juice.

While the high molecular weight esterified cellulose ethers disclosed inEP-A-0 219 426 are very desirable for good resistance against a gastricjuice, they exhibit a high viscosity when they are dissolved at a highconcentration in an organic solvent, such as a concentration of 7-10weight percent, which reduces their efficiency in coating processes. Incoating processes high concentrations of the esterified cellulose etherin an organic solvent are desired to minimize the amount of solvent thathas to be subsequently removed. On the other hand, the viscosity of thesolution should be low to facilitate spraying of the solution on thedosage forms, such as tablets, to be coated.

Moreover, a large number of presently known drugs have a low solubilityin water, so that complex techniques are required to prepare a dosageform. One known method includes dissolving such drug together with apharmaceutically acceptable water-soluble polymer, such as an esterifiedcellulose ether, in an organic solvent that is optionally blended withwater, and to spray-dry the solution. The esterified cellulose ether isaimed at reducing the crystallinity of the drug, thereby minimizing theactivation energy necessary for the dissolution of the drug, as well asestablishing hydrophilic conditions around the drug molecules, therebyimproving the solubility of the drug itself to increase itsbioavailability, i.e., its in vivo absorption by an individual uponingestion. Also in spray-drying processes high concentrations of theesterified cellulose ether in an organic solvent are desired to minimizethe amount of solvent that has to be removed. However, when theviscosity of the organic solution comprising the esterified celluloseether is high, the solution is difficult to be spray-dried and tends toclog the spray-drying device.

Accordingly, it would be highly desirable to find new esterifiedcellulose ethers which have a high molecular weight but which can stillbe efficiently used in spray-drying and coating processes.

SUMMARY

One aspect of the present invention is an esterified cellulose etherwhich comprises (i) groups of the formula —C(O)—R—COOA or (ii) acombination of aliphatic monovalent acyl groups and groups of theformula —C(O)—R—COOA, wherein R is a divalent aliphatic or aromatichydrocarbon group and A is hydrogen or a cation, which has a viscosityof up to 50 mPa·s, measured as a 10 wt % solution of the esterifiedcellulose ether in acetone at 20° C., and which has a weight averagemolecular weight M_(w) of at least 220,000 Dalton.

Yet another aspect of the present invention is an esterified celluloseether which comprises (i) groups of the formula —C(O)—R—COOA or (ii) acombination of aliphatic monovalent acyl groups and groups of theformula —C(O)—R—COOA, wherein R is a divalent aliphatic or aromatichydrocarbon group and A is hydrogen or a cation, which has a viscosityof up to 100 mPa·s, measured as a 10 wt % solution of the esterifiedcellulose ether in acetone at 20° C., and which has a weight averagemolecular weight M_(w) of at least 310,000 Dalton.

Yet another aspect of the present invention is a composition whichcomprises a liquid diluent and at least one above-described esterifiedcellulose ether.

Yet another aspect of the present invention is a solid dispersion of atleast one active ingredient in at least one above-described esterifiedcellulose ether.

Yet another aspect of the present invention is a dosage form which iscoated with at least one above-described esterified cellulose ether.

Yet another aspect of the present invention is a capsule shell whichcomprises at least one above-described esterified cellulose ether.

DESCRIPTION OF EMBODIMENTS

The esterified cellulose ether has a cellulose backbone having β-1,4glycosidically bound D-glucopyranose repeating units, designated asanhydroglucose units in the context of this invention. The esterifiedcellulose ether preferably is an esterified alkyl cellulose,hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose. This means thatin the esterified cellulose ether of the present invention, at least apart of the hydroxyl groups of the anhydroglucose units are substitutedby alkoxyl groups or hydroxyalkoxyl groups or a combination of alkoxyland hydroxyalkoxyl groups. The hydroxyalkoxyl groups are typicallyhydroxymethoxyl, hydroxyethoxyl and/or hydroxypropoxyl groups.Hydroxyethoxyl and/or hydroxypropoxyl groups are preferred. Typicallyone or two kinds of hydroxyalkoxyl groups are present in the esterifiedcellulose ether. Preferably a single kind of hydroxyalkoxyl group, morepreferably hydroxypropoxyl, is present. The alkoxyl groups are typicallymethoxyl, ethoxyl and/or propoxyl groups. Methoxyl groups are preferred.Illustrative of the above-defined esterified cellulose ethers areesterified alkylcelluloses, such as esterified methylcelluloses,ethylcelluloses, and propylcelluloses; esterifiedhydroxyalkylcelluloses, such as esterified hydroxyethylcelluloses,hydroxypropylcelluloses, and hydroxybutylcelluloses; and esterifiedhydroxyalkyl alkylcelluloses, such as esterified hydroxyethylmethylcelluloses, hydroxymethyl ethylcelluloses, ethylhydroxyethylcelluloses, hydroxypropyl methylcelluloses, hydroxypropylethylcelluloses, hydroxybutyl methylcelluloses, and hydroxybutylethylcelluloses; and those having two or more hydroxyalkyl groups, suchas esterified hydroxyethylhydroxypropyl methylcelluloses. Mostpreferably, the esterified cellulose ether is an esterified hydroxyalkylmethylcellulose, such as hydroxypropyl methylcellulose.

The degree of the substitution of hydroxyl groups of the anhydroglucoseunits by hydroxyalkoxyl groups is expressed by the molar substitution ofhydroxyalkoxyl groups, the MS(hydroxyalkoxyl). The MS(hydroxyalkoxyl) isthe average number of moles of hydroxyalkoxyl groups per anhydroglucoseunit in the esterified cellulose ether. It is to be understood thatduring the hydroxyalkylation reaction the hydroxyl group of ahydroxyalkoxyl group bound to the cellulose backbone can be furtheretherified by an alkylating agent, e.g. a methylating agent, and/or ahydroxyalkylating agent. Multiple subsequent hydroxyalkylationetherification reactions with respect to the same carbon atom positionof an anhydroglucose unit yields a side chain, wherein multiplehydroxyalkoxyl groups are covalently bound to each other by ether bonds,each side chain as a whole forming a hydroxyalkoxyl substituent to thecellulose backbone.

The term “hydroxyalkoxyl groups” thus has to be interpreted in thecontext of the MS(hydroxyalkoxyl) as referring to the hydroxyalkoxylgroups as the constituting units of hydroxyalkoxyl substituents, whicheither comprise a single hydroxyalkoxyl group or a side chain asoutlined above, wherein two or more hydroxyalkoxyl units are covalentlybound to each other by ether bonding. Within this definition it is notimportant whether the terminal hydroxyl group of a hydroxyalkoxylsubstituent is further alkylated or not; both alkylated andnon-alkylated hydroxyalkoxyl substituents are included for thedetermination of MS(hydroxyalkoxyl). The esterified cellulose ether ofthe invention generally has a molar substitution of hydroxyalkoxylgroups in the range 0.05 to 1.00, preferably 0.08 to 0.90, morepreferably 0.12 to 0.70, most preferably 0.15 to 0.60, and particularly0.21 to 0.50.

The average number of hydroxyl groups substituted by alkoxyl groups,such as methoxyl groups, per anhydroglucose unit, is designated as thedegree of substitution of alkoxyl groups, DS(alkoxyl). In theabove-given definition of DS, the term “hydroxyl groups substituted byalkoxyl groups” is to be construed within the present invention toinclude not only alkylated hydroxyl groups directly bound to the carbonatoms of the cellulose backbone, but also alkylated hydroxyl groups ofhydroxyalkoxyl substituents bound to the cellulose backbone. Theesterified cellulose ethers according to this invention preferably havea DS(alkoxyl) in the range of 1.0 to 2.5, more preferably from 1.1 to2.4, even more preferably from 1.2 to 2.2, most preferably from 1.6 to2.05, and particularly from 1.7 to 2.05.

Most preferably the esterified cellulose ether is an esterifiedhydroxypropyl methylcellulose having a DS(methoxyl) within the rangesindicated above for DS(alkoxyl) and an MS(hydroxypropoxyl) within theranges indicated above for MS(hydroxyalkoxyl).

The esterified cellulose ether of the present invention has (i) groupsof the formula —C(O)—R—COOA or (ii) a combination of aliphaticmonovalent acyl groups and groups of the formula —C(O)—R—COOA, wherein Ris a divalent aliphatic or aromatic hydrocarbon group and A is hydrogenor a cation. The cation preferably is an ammonium cation, such as NH₄ ⁺or an alkali metal ion, such as the sodium or potassium ion, morepreferably the sodium ion. Most preferably, A is hydrogen.

The aliphatic monovalent acyl groups are preferably selected from thegroup consisting of acetyl, propionyl, and butyryl, such as n-butyryl ori-butyryl.

Preferred groups of the formula —C(O)—R—COOA are

—C(O)—CH₂—CH₂—COOA, such as —C(O)—CH₂—CH₂—COOH or —C(O)—CH₂—CH₂—COO⁻Na⁺,—C(O)—CH═CH—COOA, such as —C(O)—CH═CH—COOH or —C(O)—CH═CH—COO⁻Na⁺, or—C(O)—C₆H₄—COOA, such as —C(O)—C₆H₄—COOH or —C(O)—C₆H₄—COO⁻Na⁺.

In the groups of formula —C(O)—C₆H₄—COOA the carbonyl group and thecarboxylic group are preferably arranged in ortho-positions.

Preferred esterified cellulose ethers are

i) HPMCXY, wherein HPMC is hydroxypropyl methyl cellulose, X is A(acetate), or X is B (butyrate) or X is Pr (propionate) and Y is S(succinate), or Y is P (phthalate) or Y is M (maleate), such ashydroxypropyl methyl cellulose acetate phthalate (HPMCAP), hydroxypropylmethyl cellulose acetate maleate (HPMCAM), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), or

ii) hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropylcellulose acetate succinate (HPCAS), hydroxybutyl methyl cellulosepropionate succinate (HBMCPrS), hydroxyethyl hydroxypropyl cellulosepropionate succinate (HEHPCPrS); and methyl cellulose acetate succinate(MCAS).

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is the mostpreferred esterified cellulose ether.

The esterified cellulose ethers generally have a degree of substitutionof aliphatic monovalent acyl groups, such as acetyl, propionyl, orbutyryl groups, of 0 to 1.75, preferably of 0.05 to 1.50, morepreferably of 0.10 to 1.25, and most preferably of 0.20 to 1.00.

The esterified cellulose ethers generally have a degree of substitutionof groups of formula —C(O)—R—COOA, such as succinoyl, of 0.05 to 1.6,preferably of 0.05 to 1.30, more preferably of 0.05 to 1.00, and mostpreferably of 0.10 to 0.70 or even 0.10 to 0.60.

The sum of i) the degree of substitution of aliphatic monovalent acylgroups and ii) the degree of substitution of groups of formula—C(O)—R—COOA is generally from 0.05 to 2.0, preferably from 0.10 to 1.4,more preferably from 0.20 to 1.15, most preferably from 0.30 to 1.10 andparticularly from 0.40 to 1.00.

The content of the acetate and succinate ester groups is determinedaccording to “Hypromellose Acetate Succinate”, United StatesPharmacopeia and National Formulary, NF 29, pp. 1548-1550. Reportedvalues are corrected for volatiles (determined as described in section“loss on drying” in the above HPMCAS monograph). The method may be usedin analogue manner to determine the content of propionyl, butyryl,phthalyl and other ester groups.

The content of ether groups in the esterified cellulose ether isdetermined in the same manner as described for “Hypromellose”, UnitedStates Pharmacopeia and National Formulary, USP 35, pp 3467-3469.

The contents of ether and ester groups obtained by the above analysesare converted to DS and MS values of individual substituents accordingto the formulas below. The formulas may be used in analogue manner todetermine the DS and MS of substituents of other cellulose ether esters.

${\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}} = {100 - ( {\% \mspace{14mu} {MeO}*\frac{{M( {OCH}_{3} )} - {M({OH})}}{M( {OCH}_{3} )}} ) - ( {\% \mspace{14mu} {HPO}*\frac{{M( {{OCH}_{2}{{CH}({OH})}{CH}_{3}} )} - {M({OH})}}{M( {{OCH}_{2}{{CH}({OH})}{CH}_{3}} )}} ) - ( {\% \mspace{14mu} {Acetyl}*\frac{{M( {COCH}_{3} )} - {M(H)}}{M( {COCH}_{3} )}} ) - ( {\% \mspace{14mu} {Succinoyl}*\frac{{M( {{COC}_{2}H_{4}{COOH}} )} - {M(H)}}{M( {{COC}_{2}H_{4}{COOH}} )}} )}$${{DS}({Me})} = \frac{\frac{\% \mspace{14mu} {MeO}}{M( {OCH}_{3} )}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}$${{MS}({HP})} = \frac{\frac{\% \mspace{14mu} {HPO}}{M({HPO})}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}$${{DS}({Acetyl})} = \frac{\frac{\% \mspace{14mu} {Acetyl}}{M({Acetyl})}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}$${{DS}({Succinoyl})} = \frac{\frac{\% \mspace{14mu} {Succinoyl}}{M({Succinoyl})}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}$M(MeO) = M(OCH₃) = 31.03  DaM(HPO) = M(OCH₂CH(OH)CH₃) = 75.09  DaM(Acetyl) = M(COCH₃) = 43.04  DaM(Succinoyl) = M(COC₂H₄COOH) = 101.00  Da M(AGU) = 162.14  DaM(OH) = 17.008  Da M(H) = 1.008  Da

By convention, the weight percent is an average weight percentage basedon the total weight of the cellulose repeat unit, including allsubstituents. The content of the methoxyl group is reported based on themass of the methoxyl group (i.e., —OCH₃). The content of thehydroxyalkoxyl group is reported based on the mass of the hydroxyalkoxylgroup (i.e., —O— alkylene-OH); such as hydroxypropoxyl (i.e.,—O—CH₂CH(CH₃)—OH). The content of the aliphatic monovalent acyl groupsis reported based on the mass of —C(O)—R₁ wherein R₁ is a monovalentaliphatic group, such as acetyl (—C(O)—CH₃). The content of the group offormula —C(O)—R—COOH is reported based on the mass of this group, suchas the mass of succinoyl groups (i.e., —C(O)—CH₂—CH₂—COOH).

In one aspect of the invention the esterified cellulose ethers have aweight average molecular weight M_(w) of at least 220,000 Dalton,preferably at least 230,000 Dalton, more preferably at least 250,000Dalton, and most preferably at least 300,000 Dalton, and a viscosity ofup to 50 mPa·s, preferably up to 45 mPa·s, more preferably up to 40mPa·s, and in some embodiments of the invention only up to 35 mPa·s,measured as a 10 wt % solution of the esterified cellulose ether inacetone at 20° C. In this embodiment of the invention the esterifiedcellulose ethers typically have a weight average molecular weight M_(w)of up to 350,000 Dalton, more typically up to 320,000 Dalton. In thisembodiment of the invention the esterified cellulose ethers typicallyhave a viscosity of 20 mPa·s or more, in some embodiments of theinvention 25 mPa·s or more, measured as a 10 wt % solution of theesterified cellulose ether in acetone at 20° C.

In another aspect of the invention the esterified cellulose ethers havea weight average molecular weight M_(w) of at least 310,000 Dalton,preferably least 320,000 Dalton, more preferably at least 330,000Dalton, and most preferably at least 350,000 Dalton, and a viscosity ofup to 100 mPa·s, preferably up to 85 mPa·s, more preferably up to 70mPa·s, measured as a 10 wt % solution of the esterified cellulose etherin acetone at 20° C. In this embodiment of the invention the esterifiedcellulose ethers typically have a weight average molecular weight M_(w)of up to 500,000 Dalton, more typically up to 450,000 Dalton. In thisembodiment of the invention the esterified cellulose ethers typicallyhave a viscosity of 40 mPa·s or more, more typically of 50 mPa·s ormore, and most typically of 60 mPa·s or more, measured as a 10 wt %solution of the esterified cellulose ether in acetone at 20° C.

M_(w), M_(n) and M_(z) are measured according to Journal ofPharmaceutical and Biomedical Analysis 56 (2011) 743 using a mixture of40 parts by volume of acetonitrile and 60 parts by volume of aqueousbuffer containing 50 mM NaH₂PO₄ and 0.1 M NaNO₃ as mobile phase. Themobile phase is adjusted to a pH of 8.0. The measurement of M_(w), M_(n)and M_(z) is described in more details in the Examples.

In both embodiments of the invention ways have been found to produceesterified cellulose ethers that have an above-mentioned very highweight average molecular weight in combination with the above-mentionedreasonably low viscosity in acetone. This is highly advantageous as onone hand a high molecular weight is desired, as described in EP-A-0 219426, but on the other hand a reasonably low viscosity of the esterifiedcellulose ethers, measured as a 10 wt % solution in acetone, is alsoneeded to enable the preparation of liquid compositions comprising areasonably high concentration of the esterified cellulose ether withoutan unduly high viscosity of the liquid composition. The skilled artisanswould expect that esterified cellulose ethers of high weight averagemolecular weight have a high viscosity, measured as a 10 wt % solutionin acetone, and vice versa. Providing esterified cellulose ethers thathave an above-mentioned very high weight average molecular weight incombination with the above-mentioned reasonably low viscosity in acetonesatisfied a long-felt need.

The weight average molecular weight of esterified cellulose ethers andtheir viscosity, measured as a 10 wt % solution in acetone, depend onvarious reaction parameters in the esterification of cellulose ethers.

One important reaction parameter is the viscosity of the celluloseether, measured as a 2.0 wt % solution in water at 20° C., which is usedas a starting material for preparing the esterified cellulose ethers.For producing an esterified cellulose ether of the present inventiongenerally a cellulose ether is used which has a viscosity of from 2.3 to5.0 mPa·s, preferably from 2.4 to 5.0 mPa·s, more preferably from 2.4 to4.0 mPa·s, and most preferably from 2.4 to 3.8 mPa·s, measured as a 2.0wt % solution in water at 20° C. (+/−0.1° C.). The 2.0% by weightsolution of a cellulose ether in water is prepared according to UnitedStates Pharmacopeia (USP 35, “Hypromellose”, pages 3467-3469), followedby an Ubbelohde viscosity measurement according to DIN 51562-1:1999-01(January 1999). A reasonably low viscosity of the cellulose ether usedas a starting material allows for a good miscibility of the reactionmixture used for producing the esterified cellulose ethers resulting ina homogeneous reaction mixture. Preferably a cellulose ether is usedwhich has the type of ether groups and the degree(s) of substitution ofether groups as described further above.

The cellulose ether is reacted with (i) a dicarboxylic acid anhydride or(ii) a combination of an aliphatic monocarboxylic acid anhydride and adicarboxylic acid anhydride. Preferred aliphatic monocarboxylic acidanhydrides are selected from the group consisting of acetic anhydride,butyric anhydride and propionic anhydride. Preferred dicarboxylic acidanhydrides are selected from the group consisting of succinic anhydride,maleic anhydride and phthalic anhydride. If a dicarboxylic acidanhydride and an aliphatic monocarboxylic acid anhydride are used incombination, the two anhydrides may be introduced into the reactionvessel at the same time or separately one after the other. Theesterification of the cellulose ether is preferably conducted in analiphatic carboxylic acid as a reaction diluent, such as acetic acid,propionic acid, or butyric acid. The reaction diluent can comprise minoramounts of other solvents or diluents which are liquid at roomtemperature and do not react with the cellulose ether, such as aromaticor aliphatic solvents like benzene, toluene, 1,4-dioxane, ortetrahydrofurane; or halogenated C₁-C₃ derivatives, like dichloromethane or dichloro methyl ether, but the amount of the aliphaticcarboxylic acid is preferably more than 50 percent, more preferably atleast 75 percent, and even more preferably at least 90 percent, based onthe total weight of the reaction diluent. Most preferably the reactiondiluent consists of an aliphatic carboxylic acid. Therefore, theesterification process is described below with reference to the use ofan aliphatic carboxylic acid as reaction diluent although the process isnot limited to it.

The examples below describe how to prepare the esterified celluloseethers of the present invention. Some aspects of the process forproducing these esterified cellulose ethers will be described in moregeneral terms below.

It has surprisingly been found that in all aspects of the presentinvention the molar ratio of the aliphatic carboxylic acid to thedicarboxylic acid anhydride is an important reaction parameter forachieving esterified cellulose ethers of the above-described reasonablylow viscosity in acetone, even when the esterified cellulose ethers havean above-described very high molecular weight. For producing esterifiedcellulose ethers of all aspects of the invention the utilized molarratio of (a) aliphatic carboxylic acid to (b) dicarboxylic acidanhydride, (a)/(b), is up to 12/1, typically from 7.0/1 to 12.0/1. Thisratio is lower than the ratio (a)/(b) that is typically disclosed in theprior art.

The appropriate molar ratio [aliphatic carboxylic acid/anhydroglucoseunits of cellulose ether] is also an important parameter for producingthe esterified cellulose ethers of the present invention. The utilizedmolar ratio of [aliphatic carboxylic acid/anhydroglucose units ofcellulose ether] typically is from 6.5/1 to 7.7/1.

The molar number of anhydroglucose units of the cellulose ether utilizedin the process of the present invention can be determined from theweight of the cellulose ether used as a starting material, bycalculating the average molecular weight of the substitutedanhydroglucose units from the DS(alkoxyl) and MS(hydroxyalkoxyl).

The esterification reaction is generally conducted in the presence of anesterification catalyst, preferably in the presence of an alkali metalcarboxylate, such as sodium acetate or potassium acetate. The molarratio [alkali metal carboxylate/anhydroglucose units of cellulose ether]used in the esterification process influences the weight averagemolecular weight of the esterified cellulose ether. The higher the molarratio [alkali metal carboxylate/anhydroglucose units of cellulose ether]is, the higher is generally the weight average molecular weight of theesterified cellulose ethers, if the other reaction parameters are keptconstant in the defined ranges. For producing esterified celluloseethers of the present invention the molar ratio [alkali metalcarboxylate/anhydroglucose units of cellulose ether] is typically from1.2 to 2.9.

The amount of each anhydride to be introduced into the reaction vesselis determined depending on the desired degree of esterification to beobtained in the final product, usually being 1 to 10 times thestoichiometric amounts of the desired molar degree of substitution ofthe anhydroglucose units by esterification. The molar ratio [anhydrideof a dicarboxylic acid/anhydroglucose units of the cellulose ether]generally is from 0.5/1 to 1.1/1. As indicated above, the utilized molarratio of (a) aliphatic carboxylic acid to (b) dicarboxylic acidanhydride, (a)/(b), should not be higher than 12/1, typically it is from7.0/1 to 12.0/1.

If an anhydride of a monocarboxylic acid is used, the molar ratio[anhydride of an aliphatic monocarboxylic acid/anhydroglucose units ofthe cellulose ether] generally is from 1.2/1 to 2.4/1. If an anhydrideof a monocarboxylic acid is used, the molar ratio of [anhydride of analiphatic monocarboxylic acid/anhydride of a dicarboxylic acid]typically is up to 3/1, more typically from 1.9/1 to 2.9/1.

The reaction mixture is generally heated at 60° C. to 110° C.,preferably at 70 to 100° C., for a period of time sufficient to completethe reaction, that is, typically from 2 to 25 hours, more typically from2 to 8 hours. The reaction mixture should be thoroughly mixed to providea homogeneous reaction mixture. After completion of the esterificationreaction, the reaction product can be precipitated from the reactionmixture in a known manner, for example by contacting it with a largevolume of water, such as described in U.S. Pat. No. 4,226,981,International Patent Application WO 2005/115330 or European PatentApplication EP 0 219 426. In a preferred embodiment of the invention thereaction product is precipitated from the reaction mixture as describedin U.S. Provisional Application 61/616,207, filed 27 Mar. 2012 or in itscorresponding International Patent Application PCT/US13/030394,published as WO2013/148154.

Another aspect of the present invention is a composition comprising aliquid diluent and one or more of the above described esterifiedcellulose ethers. The term “liquid diluent” as used herein means adiluent that is liquid at 25° C. and atmospheric pressure. The diluentcan be water or an organic liquid diluent or a mixture of water and anorganic liquid diluent. Preferably the amount of the liquid diluent issufficient to provide sufficient fluidity and processability to thecomposition for the desired usage, such as spray-drying or for coatingpurposes.

The term “organic liquid diluent” as used herein means an organicsolvent or a mixture of two or more organic solvents. Preferred organicliquid diluents are polar organic solvents having one or moreheteroatoms, such as oxygen, nitrogen or halogen like chlorine. Morepreferred organic liquid diluents are alcohols, for examplemultifunctional alcohols, such as glycerol, or preferably monofunctionalalcohols, such as methanol, ethanol, isopropanol or n-propanol; ethers,such as tetrahydrofuran, ketones, such as acetone, methyl ethyl ketone,or methyl isobutyl ketone; acetates, such as ethyl acetate; halogenatedhydrocarbons, such as methylene chloride; or nitriles, such asacetonitrile.

In one embodiment the composition of the present invention comprises asliquid diluent an organic diluent alone or mixed with a minor amount ofwater. In this embodiment the composition of the present inventionpreferably comprises more than 50, more preferably at least 65, and mostpreferably at least 75 weight percent of an organic liquid diluent andpreferably less than 50, more preferably up to 35, and most preferablyup to 25 weight percent of water, based on the total weight of theorganic liquid diluent and water. This embodiment of the invention is ofparticularly useful if the present invention comprises an activeingredient of poor water solubility.

In another embodiment the composition of the present invention comprisesas liquid diluent water alone or mixed with a minor amount of an organicliquid diluent as described above. In this embodiment the composition ofthe present invention preferably comprises at least 50, more preferablyat least 65, and most preferably at least 75 weight percent of water andpreferably up to 50, more preferably up to 35, and most preferably up to25 weight percent of an organic liquid diluent, based on the totalweight of the organic liquid diluent and water. This embodiment of theinvention is particularly useful for providing coatings or capsules fromaqueous compositions comprising the esterified cellulose ether of thepresent invention. When preparing an aqueous solution, it is preferredthat at least a portion of the groups of formula —C(O)—R—COOA are intheir salt form.

The composition of the present invention comprising a liquid diluent andone or more of the above described esterified cellulose ethers is usefulas an excipient system for active ingredients and particularly useful asan intermediate for preparing an excipient system for activeingredients, such as fertilizers, herbicides or pesticides, orbiologically active ingredients, such as vitamins, herbals and mineralsupplements and drugs. Accordingly, the composition of the presentinvention preferably comprises one or more active ingredients, mostpreferably one or more drugs. The term “drug” is conventional, denotinga compound having beneficial prophylactic and/or therapeutic propertieswhen administered to an animal, especially humans. Preferably, the drugis a “low-solubility drug”, meaning that the drug has an aqueoussolubility at physiologically relevant pH (e.g., pH 1-8) of about 0.5mg/mL or less. The invention finds greater utility as the aqueoussolubility of the drug decreases. Thus, compositions of the presentinvention are preferred for low-solubility drugs having an aqueoussolubility of less than 0.1 mg/mL or less than 0.05 mg/mL or less than0.02 mg/mL, or even less than 0.01 mg/mL where the aqueous solubility(mg/mL) is the minimum value observed in any physiologically relevantaqueous solution (e.g., those with pH values between 1 and 8) includingUSP simulated gastric and intestinal buffers. The active ingredient doesnot need to be a low-solubility active ingredient in order to benefitfrom this invention, although low-solubility active ingredientsrepresent a preferred class for use with the invention. An activeingredient that exhibits appreciable aqueous solubility in the desiredenvironment of use may have an aqueous solubility up to 1 to 2 mg/mL, oreven as high as 20 to 40 mg/mL. Useful low-solubility drugs are listedin the International Patent Application WO 2005/115330, pages 17-22.

The liquid composition of the present invention preferably comprisesfrom 1 to 40 percent, more preferably from 3 to 30 percent, even morepreferably from 4 to 25 percent, and most preferably from 5 to 20percent of at least one esterified cellulose ether as described above,from 40 to 99 percent, more preferably from 50 to 96.9 percent, evenmore preferably from 65 to 95.5 percent and most preferably from 65 to94 percent of a liquid diluent described further above, and from 0 to 40percent, more preferably from 0.1 to 40 percent, even more preferablyfrom 0.5 to 25 percent, and most preferably from 1 to 15 percent of anactive ingredient, based on the total weight of the composition. Thereasonably low viscosity of the esterified cellulose ether of thepresent invention, measured as a 10 wt % solution in acetone at 20° C.,allows the incorporation of a higher concentration of the esterifiedcellulose ether, i.e., a higher ratio of esterified cellulose ether toliquid diluent, than known esterified cellulose ethers of comparableweight average molecular weight while still providing a liquidcomposition of reasonably low viscosity. This can be utilized in twoways to produce solid dispersions of an active ingredient in anesterified cellulose ether: 1. Either the ratio of esterified celluloseether/active ingredient is kept the same as in known, more dilutecompositions. In this case a higher concentration of the esterifiedcellulose ether also leads to a higher concentration of the activeingredient in the liquid composition, and, accordingly to an increasedthroughput of the active ingredient in the production of soliddispersions while maintaining the same stability of the activeingredient. 2. Alternatively, only the concentration of the esterifiedcellulose ether in the liquid composition is increased, but not theconcentration of the active ingredient. This leads to a higher ratio ofesterified cellulose ether/active ingredient, which leads to an improvedstabilization of the active ingredient in the matrix of the esterifiedcellulose ether upon removal of the liquid diluent without decreasingthe throughput of the active ingredient. This means that formulators canoperate at a higher content of the esterified cellulose ether in theliquid formulation—without the need to reduce the content of the activeingredient—in order to achieve enhanced stabilization of the amorphousstate of an active ingredient in a solid dosage form. The esterifiedcellulose ethers of the present invention allow a high loading of theactive ingredient in the liquid composition while still achieving areasonably high throughput in preparing a solid dispersion. Theproduction of semi-ordered instead of amorphous dispersions to achieve ahigher active ingredient throughput as proposed in WO2004/014342, page13, last paragraph, is not necessary.

In one aspect of the invention the composition comprising at least oneesterified cellulose ether as described above, one or more activeingredients and optionally one or more adjuvants can be used in liquidform, for example in the form of a suspension, a slurry, a sprayablecomposition, or a syrup. The liquid composition is useful, e.g., fororal, ocular, topical, rectal or nasal applications. The liquid diluentshould generally be pharmaceutically acceptable, such as ethanol orglycerol, optionally mixed with water as described above. The lowviscosity of the esterified cellulose ether in acetone or anotherorganic solvent significantly improves the handling of the liquidcomposition, such as its ability of being poured or pumped.

In another aspect of the invention the liquid composition of the presentinvention is used for producing a solid dispersion comprising at leastone active ingredient, such as a drug described further above, at leastone esterified cellulose ether as described above and optionally one ormore adjuvants. The solid dispersion is produced by removing the liquiddiluent from the composition. The low viscosity of the esterifiedcellulose ether in acetone or another organic solvent allows theincorporation of a high concentration of the esterified cellulose ether,and accordingly a high concentration of a drug, into the compositionwhile still maintaining a reasonably low viscosity of the liquidcomposition. This is highly advantageous for achieving a high throughputwhen the liquid composition is used for coating purposes or when thecomprising the esterified cellulose ether is subjected to spray-drying,for example for preparing solid dispersions comprising an activeingredient and an esterified cellulose ether. Moreover, liquidformulations using a high ratio of esterified cellulose ether to activeingredient, as described above, can be formulated with spray drying. Ahigh ratio of esterified cellulose ether to active ingredient is desiredin maintaining supersaturation of poorly soluble active ingredients andfor increasing its bioavailability.

One method of removing the liquid diluent from the liquid composition isby casting the liquid composition into a film or a capsule or byapplying the liquid composition onto a solid carrier that in turn maycomprise an active ingredient. The use of the liquid composition of thepresent invention for coating purposes is a preferred aspect of thepresent invention.

A preferred method of producing a solid dispersion is by spray-drying.The term “spray-drying” refers to processes involving breaking up liquidmixtures into small droplets (atomization) and rapidly removing solventfrom the mixture in a spray-drying apparatus where there is a strongdriving force for evaporation of solvent from the droplets. Spray-dryingprocesses and spray-drying equipment are described generally in Perry'sChemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984).More details on spray-drying processes and equipment are reviewed byMarshall, “Atomization and Spray-Drying,” 50 Chem. Eng. Prog. Monogr.Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition1985). A useful spray-drying process is described in the InternationalPatent Application WO 2005/115330, page 34, line 7-page 35, line 25.Alternatively, the solid dispersion of the present invention may beprepared by i) blending a) at least one esterified cellulose etherdefined above, b) one or more active ingredients and c) one or moreoptional additives, and ii) subjecting the blend to extrusion. The term“extrusion” as used herein includes processes known as injectionmolding, melt casting and compression molding. Techniques for extruding,preferably melt-extruding compositions comprising an active ingredientsuch as a drug are known and described by Joerg Breitenbach, Meltextrusion: from process to drug delivery technology, European Journal ofPharmaceutics and Biopharmaceutics 54 (2002) 107-117 or in EuropeanPatent Application EP 0 872 233. The solid dispersion of the presentinvention preferably comprises from 20 to 99.9 percent, more preferablyfrom 30 to 98 percent, and most preferably from 60 to 95 percent of anesterified cellulose ether a) as described above, and preferably from0.1 to 80 percent, more preferably from 2 to 70 percent, and mostpreferably from 5 to 40 percent of an active ingredient b), based on thetotal weight of the esterified cellulose ether a) and the activeingredient b). The combined amount of the esterified cellulose ether a)and the active ingredient b) is preferably at least 70 percent, morepreferably at least 80 percent, and most preferably at least 90 percent,based on the total weight of the solid dispersion. The remaining amount,if any, consists of one or more of the adjuvants c) as described below.The solid dispersion can comprise one or more of the esterifiedcellulose ethers a), one or more of the active ingredients b), andoptionally one or more of the adjuvants c), however their total amountis generally within the above-mentioned ranges.

Once the solid dispersion comprising at least one active ingredient inat least one esterified cellulose ether has been formed, severalprocessing operations can be used to facilitate incorporation of thedispersion into a dosage form. These processing operations includedrying, granulation, and milling. The inclusion of optional adjuvants inthe solid dispersion may be useful in order to formulate the compositioninto dosage forms. The solid dispersion of the present invention may bein various forms, such as in the form of strands, pellets, granules,pills, tablets, caplets, microparticles, fillings of capsules orinjection molded capsules or in the form of a powder, film, paste,cream, suspension or slurry.

The amount of the active ingredient in the dosage form is generally isat least 0.1 percent, preferably at least 1 percent, more preferably atleast 3 percent, most preferably at least 5 percent and generally up to70 percent, preferably up to 50 percent, more preferably up to 30percent, most preferably up to 25 percent, based on the total weight ofthe dosage form.

In another aspect of the invention the composition of the presentinvention comprising a liquid diluent and one or more of the abovedescribed esterified cellulose ethers may be used for coating dosageforms, such as tablets, granules, pellets, caplets, lozenges,suppositories, pessaries or implantable dosage forms, to form a coatedcomposition. If the composition of the present invention comprises anactive ingredient, such as a drug, drug layering can be achieved, i.e.,the dosage form and the coating may comprise different activeingredients for different end-uses and/or having different releasekinetics.

In yet another aspect of the invention the composition of the presentinvention comprising a liquid diluent and one or more of the abovedescribed esterified cellulose ethers may be used for the manufacture ofcapsules in a process which comprises the step of contacting the liquidcomposition with dipping pins.

The liquid composition and the solid dispersion of the present inventionmay further comprise optional additives, such as coloring agents,pigments, opacifiers, flavor and taste improvers, antioxidants, and anycombination thereof. Optional additives are preferably pharmaceuticallyacceptable. Useful amounts and types of one or more optional adjuvantsare generally known in the art and depend on the intended end-use of theliquid composition or the solid dispersion of the present invention.

Some embodiments of the invention will now be described in detail in thefollowing Examples.

EXAMPLES

Unless otherwise mentioned, all parts and percentages are by weight. Inthe Examples the following test procedures are used.

Viscosity of Hydroxypropyl Methyl Cellulose (HPMC) Samples

The viscosity of the HPMC samples was measured as a 2.0% by weightsolution in water at 20° C.±0.1° C. The 2.0% by weight HPMC solution inwater was prepared according to United States Pharmacopeia (USP 35,“Hypromellose”, pages 3467-3469), followed by an Ubbelohde viscositymeasurement according to DIN 51562-1:1999-01 (January 1999).

Viscosity of Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS)

The 2.0% by weight solution of the HPMCAS in 0.43 wt % aqueous NaOH wasprepared as described in“Hypromellose Acetate Succinate, United StatesPharmacopia and National Formulary, NF 29, pp. 1548-1550”, followed byan Ubbelohde viscosity measurement at 20° C. according to DIN51562-1:1999-01 (January 1999).

The 10 wt % solution of the esterified cellulose ether in acetone wasprepared by first determining the loss on drying of the HPMCAS according“Hypromellose Acetate Succinate, United States Pharmacopia and NationalFormulary, NF 29, pp. 1548-1550”. Subsequently 10.00 g HPMCAS, based onits dry weight, was mixed with 100 g of acetone under vigorous stirringat room temperature. The mixture was rolled on a roller mixer for about24 hours. The solution was centrifuged at 2000 rpm for 3 minutes using aMegafuge 1.0 centrifuge, commercially available from Heraeus HoldingGmbH, Germany, followed by an Ubbelohde viscosity measurement at 20° C.according to DIN 51562-1:1999-01 (January 1999).

Content of Ether and Ester Groups of HPMCAS

The content of ether groups in the esterified cellulose ether wasdetermined in the same manner as described for “Hypromellose”, UnitedStates Pharmacopeia and National Formulary, USP 35, pp 3467-3469.

The ester substitution with acetyl groups (—CO—CH₃) and the estersubstitution with succinoyl groups (—CO—CH₂—CH₂—COOH) were determinedaccording to Hypromellose Acetate Succinate, United States Pharmacopiaand National Formulary, NF 29, pp. 1548-1550”. Reported values for estersubstitution were corrected for volatiles (determined as described insection “loss on drying” in the above HPMCAS monograph).

Determination of M_(w), M_(n) and M_(z) of HPMCAS

Mw, Mn and Mz were measured according to Journal of Pharmaceutical andBiomedical Analysis 56 (2011) 743 unless stated otherwise. The mobilephase was a mixture of 40 parts by volume of acetonitrile and 60 partsby volume of aqueous buffer containing 50 mM NaH2PO4 and 0.1 M NaNO3.The mobile phase was adjusted to a pH of 8.0. Solutions of the celluloseether esters were filtered into a HPLC vial through a syringe filter of0.45 μm pore size.

More specifically, the utilized Chemicals and solvents were:

Polyethylene oxide standard materials (abbreviated as PEOX 20 K and PEOX30 K) were purchased from Agilent Technologies, Inc. Palo Alto, Calif.,catalog number PL2083-1005 and PL2083-2005.

Acetonitrile (HPLC grade ≧99.9%, CHROMASOL plus), catalog number 34998,sodium hydroxide (semiconductor grade, 99.99%, trace metal base),catalog number 306576, water (HPLC grade, CHROMASOLV Plus) catalognumber 34877 and sodium nitrate (99.995%, trace metal base) catalognumber 229938 were purchased from Sigma-Aldrich, Switzerland.

Sodium dihydrogen phosphate (≧99.999% TraceSelect) catalog number 71492was purchased from FLUKA, Switzerland.

The normalization solution of PEOX20 K at 5 mg/mL, the standard solutionof PEOX30 K at 2 mg/mL, and the sample solution of HPMCAS at 2 mg/mLwere prepared by adding a weighed amount of polymer into a vial anddissolving it with a measured volume of mobile phase. All solutions wereallowed to dissolve at room temperature in the capped vial for 24 h withstirring using a PTFE-coated magnetic stirring bar.

The normalization solution (PEOX 20k, single preparation, N) and thestandard solution (PEOX30 K, double preparation, S1 and S2) werefiltered into a HPLC vial through a syringe filter of 0.02 μm pore sizeand 25 mm diameter (Whatman Anatop 25, catalog number 6809-2002),Whatman.

The test sample solution (HPMCAS, prepared in duplicate, T1, T2) and alaboratory standard (HPMCAS, single preparation, LS) were filtered intoa HPLC vial through a syringe filter of 0.45 μm pore size (Nylon, e.g.Acrodisc 13 mm VWR catalog number 514-4010).

Chromatographic condition and run sequence were conducted as describedby Chen, R. et al.; Journal of Pharmaceutical and Biomedical Analysis 56(2011) 743-748). The SEC-MALLS instrument set-up included a HP1100 HPLCsystem from Agilent Technologies, Inc. Palo Alto, Calif.; a DAWN HeleosII 18 angle laser light scattering detector and a OPTILAB rex refractiveindex detector, both from Wyatt Technologies, Inc. Santa Barbara, Calif.The analytical size exclusion column (TSK-GEL® GMPWXL, 300×7.8 mm) waspurchased from Tosoh Bioscience. Both the OPTILAB and the DAWN wereoperated at 35° C. The analytical SEC column was operated at roomtemperature (24±5° C.). The mobile phase was a mixture of 40 volumeparts of acetonitrile and 60 volume parts of aqueous buffer containing50 mM NaH2PO4 and 0.1 M NaNO3 prepared as follows:

Aqueous buffer: 7.20 g of sodium dihydrogen phosphate and 10.2 g ofsodium nitrate were added to 1.2 L purified water in a clean 2 L glassbottle under stirring until dissolution.

Mobile phase: 800 mL of acetonitrile were added to 1.2 L of the aqueousbuffer prepared above, and stirred until a good mixture was achieved andthe temperature equilibrated to ambient temperature.

The mobile phase was pH adjusted to 8.0 with 10M NaOH and filteredthrough a 0.2 m nylon membrane filter. The flow rate was 0.5 mL/min within-line degassing. The injection volume was 100 μL and the analysis timewas 35 min.

The MALLS data were collected and processed by Wyatt ASTRA software(version 5.3.4.20) using dn/dc value (refractive index increment) of0.120 mL/g for HPMCAS. The light scattering signals of detector Nos.1-4, 17, and 18) were not used in the molecular weight calculation. Arepresentative chromatographic run sequence is given below: B, N, LS, S1(5×), S2, T1 (2×), T2 (2×), T3 (2×), T4 (2×), S2, T5 (2×), etc., S2, LS,W, where, B represents blank injection of mobile phase, N1 representsnormalization solution; LS represents a laboratory standard HPMCAS; S1and S2 represent standard solutions one and two, respectively; T1, T2,T3, T4, and T5 represent test sample solutions and W represents waterinjection. (2×) and (5×) denote the number of injections of the samesolution.

Both the OPTILAB and the DAWN were calibrated periodically according tothe manufacturer's recommended procedures and frequency. A 100 μLinjection of a 5 mg/mL polyethylene oxide standard (PEOX20 K) wasemployed for normalizing all angle light scattering detectors relativeto 90° detector for each run sequence.

Use of this mono-dispersed polymer standard also enabled the volumedelay between the OPTILAB and the DAWN to be determined, permittingproper alignment of the light scattering signals to the refractive indexsignal. This is necessary for the calculation of the weight-averagedmolecular weight (Mw) for each data slice.

Production of Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS)of Examples 1-6

Glacial acetic acid, acetic anhydride, a hydroxypropyl methylcellulose(HPMC), succinic anhydride and sodium acetate (water free) wereintroduced in the amounts listed in Table 1 below into a reaction vesselunder thorough stirring to produce a homogeneous reaction mixture. TheHPMC had a methoxyl and hydroxypropoxyl substitution and a viscosity,measured as a 2% solution in water at 20° C., as listed in Table 2below. The HPMC is commercially available from The Dow Chemical Companyas Methocel E3 LV Premium cellulose ether.

The mixture was heated at 85° C. with agitation for 3 or 3.5 hours, aslisted in Table 1 below, to effect esterification. x L of water wasadded to the reactor under stirring to precipitate the HPMCAS. Theprecipitated product was removed from the reactor and washed with y L ofwater by applying high shear mixing using an Ultra-Turrax stirrerS50-G45 running at 5200 rpm. The washing was conducted in severalportions with intermediate filtration steps to obtain HPMCAS of veryhigh purity. The HPMCAS products should be washed and filtrated untiltheir viscosity is substantially constant (10 wt. % in acetone). Thenumbers of L of water x and y are listed in Table 1 below. After thelast filtration step the product was dried at 50° C. overnight.

Production of HPMCAS of Comparative Examples A and B

The production of HPMCAS according to Comparative Examples A and B wascarried out as in Examples 1 to 6, except that the type of HPMC and theweight ratios of glacial acetic acid, acetic anhydride, HPMC, succinicanhydride and sodium acetate (water free) were used as disclosed inExample 2 of European Patent Application EP 0219 426 A2. The usedamounts are listed in Table 1 below.

The HPMC used in Comparative Example A had a viscosity of 6.0 mPa's,measured as a 2% solution in water at 20° C., 28.2% by weight ofhydroxypropoxyl groups and 9.0% by weight of methoxyl groups. This HPMCis commercially available from The Dow Chemical Company as Methocel E6LV Premium cellulose ether. The HPMC used in Comparative Example B had aviscosity of 3.1 mPa's, measured as a 2% solution in water at 20° C.,9.3% by weight of hydroxypropoxyl groups and 28.2% by weight of methoxylgroups. This HPMC is commercially available from The Dow ChemicalCompany as Methocel E3 LV Premium cellulose ether.

The mixture was heated at 85° C. with agitation for 3.5 hours to effectesterification. x L of water was added to the reactor under stirring toprecipitate the HPMCAS. The precipitated product was removed from thereactor and washed with y L of water by applying high shear mixing usingan Ultra-Turrax stirrer S50-G45 running at 5200 rpm. The numbers ofwater x and y are listed in Table 1 below. The product was isolated byfiltration and dried at 55° C. for 12 h.

The obtained ester substitutions % acetyl and % succinoyl in ComparativeExamples A and B were significantly different from those disclosed inExample 2 of European Patent Application EP 0219 426 A2. Therefore,Comparative Examples A and B were repeated. The obtained estersubstitutions % acetyl and % succinoyl in the repeated Examples A and Bwere substantially the same as in the first set of Comparative ExamplesA and B. The results in Tables 2 show the average of the two runs ofComparative Examples A and B.

Production of HPMCAS of Comparative Examples C and D

The production of HPMCAS according to Comparative Examples C and D wascarried out as in Examples 1 to 6, except that the weight ratios ofglacial acetic acid, acetic anhydride, HPMC, succinic anhydride andsodium acetate (water free) were used as disclosed International PatentApplication WO 2005/115330, pages 51 and 52, polymers 1 and 3. Theproduct was obtained, separated and washed as described in InternationalPatent Application WO 2005/115330. The reaction mixture was quenchedinto 2.4 L of water, precipitating the polymer. An additional 1 L ofwater was used to complete the precipitation for example C only. Thepolymer was then isolated and washed with 3×300 mL of water. Then thepolymer was dissolved in 600 mL of acetone and again precipitated in 2.4L of water. To complete precipitation another 1 L of water was added.

Comparative Examples E to G

As disclosed in International Patent Application WO 2011/159626 on pages1 and 2, HPMCAS is currently commercially available from Shin-EtsuChemical Co., Ltd. (Tokyo, Japan), known by the trade name “AQOAT”.Shin-Etsu manufactures three grades of AQOAT polymers that havedifferent combinations of substituent levels to provide entericprotection at various pH levels, AS-L, AS-M, and AS-H, typicallyfollowed by the designation “F” for fine or “G”, such as AS-LF or AS-LG.Their sales specifications are listed below.

Properties of AQOAT Polymers as Listed in WO 2011/159626

Designation of analyzed commercial samples: Comparative Example E F GPublished Composition of AQOAT polymers (wt %) Substituent contentL-Grade M-Grade H-Grade Methoxyl 20.0-24.0 21-0-25.0 22.0-26.0Hydroxypropoxyl 5.0-9.0 5.0-9.0  6.0-10.0 Acetyl 5.0-9.0  7.0-11.010.0-14.0 Succinoyl 14.0-18.0 10-14 4.0-8.0

Samples of the commercially available materials were analyzed asdescribed further above.

Production of HPMCAS of Comparative Examples H-J

The production, purification and isolation of HPMCAS according toComparative Examples H-J was carried out as in Examples 4-6 of U.S.Provisional Application 61/692,939, filed 24 Aug. 2012 or itscorresponding International Patent Application PCT/US13/055188, filed 15Aug. 2013, published as _.

Production of HPMCAS of Comparative Examples K-M

The production, purification and isolation of HPMCAS according toComparative Examples K-M was carried out as in Examples 2-4 of U.S.Provisional Application 61/692,932, filed 24 Aug. 2012 or itscorresponding International Patent Application PCT/US13/055183, filed 15Aug. 2013, published as _.

Comparative Examples N, O-1, O-2, P-1 and P-2

HPMCAS samples were produced as described on pages 34 and 35 of WO2011/159626. In Comparative Example N the recipe for HPMCAS-K(1) wasexactly repeated. In Comparative Examples O-1 and O-2 the recipe forHPMCAS-K(2) and in Comparative Examples P-1 and P-2 the recipe forHPMCAS-K(3) were exactly repeated. Comparative Examples O and P wereeach conducted twice and reported as O-1, O-2, P-1 and P-2 respectivelysince the results in Comparative Examples O-1 and P-1 for DOS_(Ac) andDOS_(s) deviated from the results reported in WO 2011/159626 forHPMCAS-K(2) and HPMCAS-K(3).

The properties of the HPMCAS produced according to Examples 1-6 andcomparative Examples A-D, H-M, N, O-1, O-2, P-1 and P-2 and theproperties of the commercially available Comparative Examples E to G arelisted in Table 2 below.

In Table 2 below the abbreviations have the following meanings:

DS_(M)=DS(methoxyl): degree of substitution with methoxyl groups;MS_(HP)=MS(hydroxypropoxyl): molar subst. with hydroxypropoxyl groups;DOS_(Ac): degree of substitution of acetyl groups;DOS_(s): degree of substitution of succinoyl groups

TABLE 1 HPMC, Succinic Acetic Acetic 2% acetic acid anhydride acid/anhydride Sodium acetate viscosity mol/ mol/ succinic mol/ mol/ Heating(Comp.) HPMC* in water mol mol anhydride mol mol at 85° C. x L of y L ofExample g mol (mPa · s) g HPMC g HPMC mol/mol g HPMC g HPMC hours waterwater 1 230 1.14 3.1 517 7.6 117.9 1.04 7.3 235.9 2.12 230.0 2.47 3 2.1632 2 230 1.14 3.1 516 7.6 107.3 0.94 8.1 260.0 2.33 230.0 2.47 3 2.8 303 195 0.96 3.18 380 6.6 54.6 0.57 11.6 150.0 1.59 100.0 1.27 3.5 1.8 114 230 1.14 3.1 518 7.6 72.2 0.64 11.9 139.2 1.25 230.0 2.47 3 2.3 26 5230 1.14 3.41 520 7.6 80.0 0.70 10.9 220.0 1.98 270.0 2.90 3 2.16 12 6230 1.14 3.41 469 6.9 81.0 0.71 9.7 199.0 1.79 200.0 2.15 3 2.16 15 A100 0.49 6.0 300 10.1 25.0 0.51 19.8 38 0.78 80 1.97 3.5 1.2 12 B 2000.96 3.1 600 10.2 50.0 0.51 19.8 76 0.78 160 1.97 3.5 2.4 11 C 80 0.403.1 420 17.7 18.9 0.48 36.9 640.2 16.53 40.43 1.25 21.75 See Comp. D 800.40 3.1 420 17.7 13.2 0.33 53.6 432.8 11.17 40.43 1.25 21.75 Examples Cand D above H¹⁾ 230 1.14 3.1 521 7.6 64.4 0.57 13.3 299.0 2.69 283.13.04 3 2.1 20 I¹⁾ 230 1.14 3.1 521 7.6 64.4 0.57 13.3 299.0 2.69 306.73.29 3 2.1 20 J¹⁾ 150 0.74 3.1 340 7.6 42.0 0.57 13.3 195.0 2.69 215.43.54 3 2.1 16.5 K¹⁾ 230 1.14 3.1 350 5.1 38.8 0.34 15.0 142.6 1.28 50.00.54 3.5 2.3 16 L¹⁾ 230 1.14 3.1 330 4.8 38.8 0.34 14.1 142.6 1.28 50.00.54 3.5 2.3 16 M¹⁾ 230 1.14 3.1 330 4.8 38.8 0.34 14.1 142.6 1.28 50.00.54 3.5 2.3 16 *calculated on the dried basis ¹⁾Subject matter ofearlier filed co-pending patent applications

TABLE 2 Ether Molecular weight 10% viscosity Ether Substitution Estersubstitution Sub- Ester (Comp.) (kDA) in acetone Methoxyl Hydroxy-Acetyl Succinoyl stitution substitution Example Mn Mw Mz (mPa · s) (%)Propoxyl, % (%) (%) DS_(M) MS_(HP) DOS_(Ac) DOS_(s) 1 80 311 1530 46.321.6 6.8 6.5 20.0 1.92 0.25 0.42 0.55 2 57 229 1230 36.5 22.1 7.0 7.217.8 1.93 0.25 0.45 0.48 3 83 258 1156 39.9 22.7 7.2 7.9 15 1.93 0.250.48 0.39 4 89 337 1770 67 22.0 7.0 6.2 18.4 1.90 0.25 0.39 0.49 5 175483 1802 68 22.3 7.0 7.9 16.9 1.94 0.25 0.50 0.45 6 133 393 1519 67 22.26.9 7.3 17.7 1.93 0.25 0.46 0.47 A 87 270 1060 638 21.9 7.2 5.6 16.81.83 0.25 0.34 0.43 B 26 65 329 16.6 22.9 7.3 5.7 16.0 1.91 0.25 0.340.41 C 23 51 462 12.8 22.3 7.4 11.7 11.7 1.90 0.26 0.72 0.31 D 22 541158 13.5 22.6 7.1 12.6 9.1 1.87 0.24 0.75 0.23 E 33 153 889 27.7 22.57.0 8.1 14.7 1.90 0.24 0.49 0.38 F 27 114 654 22.9 23.1 7.3 9.3 10.61.88 0.24 0.54 0.26 G 29 137 821 29.8 23.6 7.2 11.6 7.9 1.90 0.24 0.670.19 H¹⁾ 75 248 1235 74 22.6 7.2 10.9 12.4 1.93 0.25 0.67 0.32 I¹⁾ 81266 1297 87 22.4 7.2 10.9 12.5 1.91 0.25 0.67 0.33 J¹⁾ 97 305 1414 11422.5 7.2 10.8 12.4 1.91 0.25 0.66 0.32 K¹⁾ 77 230 1048 54 23.3 7.5 8.910.6 1.89 0.25 0.52 0.26 L¹⁾ 96 285 1185 236 23.3 7.5 8.8 11 1.90 0.250.52 0.27 M¹⁾ 103 299 1212 967 22.9 7.4 8.5 10.2 1.83 0.24 0.49 0.25 N94 427 2592 insoluble 15.7 6.2 12.1 20.8 1.47 0.24 0.82 0.60 O-1recovery rate only 71% partially 16.2 6.3 14.3 16.6 1.47 0.24 0.94 0.46insoluble O-2 recovery rate only 71% partially 15.8 6.0 14.8 17.1 1.450.23 0.98 0.48 insoluble P-1 39 234 2701 partially 17.2 6.6 19.1 8.21.49 0.24 1.19 0.22 insoluble P-2 25 143 2280 partially 16.9 6.4 19.08.7 1.47 0.23 1.19 0.23 insoluble ¹⁾Subject matter of earlier filedco-pending patent applications

European Patent Application EP 0 219 426 discloses that the HPMCAS ofComparative Example A is useful as an enterosoluble film-coatingmaterial on tablets which has resistance against a simulated gastricjuice, whereas tablets coated with HPMCAS of Comparative Example Bdisintegrate in simulated gastric juice. The HPMCAS of ComparativeExample A has a higher weight average molecular weight than ComparativeExample B. HPMCAS of a high weight average molecular weight is evidentlyvery desirable, however the HPMCAS of Comparative Example A has a muchhigher viscosity, measured as a 10 wt. % solution in acetone, and can beless efficiently processed in spray-drying or coating processes.

The comparison between Examples 1-3 on one hand and Comparative ExamplesA and H-M on the other hand illustrates that the HPMCAS of Examples 1-3have weight average molecular weights in the same range as the HPMCAS ofComparative Examples A and H-M but a much lower viscosity, measured as a10 wt. % solution in acetone.

The comparison between Examples 4-6 on one hand and Comparative ExamplesA and H-M on the other hand illustrates that the HPMCAS of Examples 4-6have higher weight average molecular weights than the HPMCAS ofComparative Examples A and H-M, and the HPMCAS of Examples 4-6 exhibit a10% viscosity in acetone that is comparable to or even significantlylower than the 10% viscosity in acetone of Comparative Examples A andH-M.

The HPMCAS of Comparative Examples B-G have a lower viscosity, measuredas a 10 wt. % solution in acetone, than the HPMCAS of Examples 1-6, butthe HPMCAS of Comparative Examples B-G have much lower weight averagemolecular weights than the HPMCAS of Examples 1-6.

The HPMCAS of Comparative Examples N, O-1, O-2, P-1 and P-2 were not oronly partially soluble in acetone at a concentration of 10 wt-%. InComparative Examples O-1 and O-2 the recovery rate in the utilized HPLCmethod was too low to make a reasonably reliable M_(w), M_(n) and M_(z)determination. Recovery rate=[weight of HPMCAS recovered from HPLCcolumn/weight of HPMCAS introduced into HPLC column]×100.

1. An esterified cellulose ether comprising (i) groups of the formula—C(O)—R—COOA or (ii) a combination of aliphatic monovalent acyl groupsand groups of the formula —C(O)—R—COOA, wherein R is a divalentaliphatic or aromatic hydrocarbon group and A is hydrogen or a cation,having a viscosity of up to 50 mPa·s, measured as a 10 wt % solution ofthe esterified cellulose ether in acetone at 20° C., and having a weightaverage molecular weight M_(w) of at least 220,000 Dalton.
 2. Theesterified cellulose of claim 1 having a weight average molecular weightM_(w) of at least 250,000 Dalton.
 3. The esterified cellulose ether ofclaim 1 having a viscosity of up 40 mPa·s, measured as a 10 wt %solution of the esterified cellulose ether in acetone at 20° C.
 4. Anesterified cellulose ether comprising (i) groups of the formula—C(O)—R—COOA or (ii) a combination of aliphatic monovalent acyl groupsand groups of the formula —C(O)—R—COOA, wherein R is a divalentaliphatic or aromatic hydrocarbon group and A is hydrogen or a cation,having a viscosity of up to 100 mPa·s, measured as a 10 wt % solution ofthe esterified cellulose ether in acetone at 20° C., and having a weightaverage molecular weight M_(w) of at least 310,000 Dalton.
 5. Theesterified cellulose ether of claim 4 having a weight average molecularweight M_(w) of at least 350,000 Dalton.
 6. The esterified celluloseether of claim 4 having a viscosity of up 80 mPa·s, measured as a 10 wt% solution of the esterified cellulose ether in acetone at 20° C.
 7. Theesterified cellulose ether of claim 1 wherein the aliphatic monovalentacyl groups are acetyl, propionyl or butyryl groups and the groups ofthe formula —C(O)—R—COOA are —C(O)—CH₂—CH₂—COOA, —C(O)—CH═CH—COOA, or—C(O)—C₆H₄—COOA groups.
 8. The esterified cellulose ether of claim 1being hydroxypropyl methyl cellulose acetate succinate.
 9. A compositioncomprising a liquid diluent and at least one esterified cellulose etherof claim
 1. 10. (canceled)
 11. The composition of claim 9 comprisingfrom 5 to 20 percent of at least one esterified cellulose ether, from 65to 94 percent of a liquid diluent, and from 1 to 15 percent of an activeingredient, based on the total weight of the composition.
 12. A soliddispersion comprising at least one active ingredient and at least oneesterified cellulose ether of claim
 1. 13. (canceled)
 14. A dosage formbeing coated with at least one esterified cellulose ether of claim 1.15. A capsule shell comprising at least one esterified cellulose etherof claim
 1. 16. The esterified cellulose ether of claim 4 wherein thealiphatic monovalent acyl groups are acetyl, propionyl or butyryl groupsand the groups of the formula —C(O)—R—COOA are —C(O)—CH₂—CH₂—COOA,—C(O)—CH═CH—COOA, or —C(O)—C₆H₄—COOA groups.
 17. The esterifiedcellulose ether of claim 4 being hydroxypropyl methyl cellulose acetatesuccinate.
 18. A composition comprising a liquid diluent and at leastone esterified cellulose ether of claim
 4. 19. The composition of claim18 comprising from 5 to 20 percent of at least one esterified celluloseether, from 65 to 94 percent of a liquid diluent, and from 1 to 15percent of an active ingredient, based on the total weight of thecomposition.
 20. A solid dispersion comprising at least one activeingredient and at least one esterified cellulose ether of claim
 4. 21. Adosage form being coated with at least one esterified cellulose ether ofclaim
 4. 22. A capsule shell comprising at least one esterifiedcellulose ether of claim 4.